Increasing evidence has accumulated documenting the existence of abnormalities in the immune system of patients with diabetes mellitus and in animal models of diabetes. Our laboratory and others have documented the existence of marked abnormalities in immunological function in genetically obese, hyperinsulinemic, diabetic C57BL/KsJ-db+/db+ mice and in hypoinsulinemic mice with chemically-induced or EMC virus-induced diabetes. In all three models, the alterations in immunological function appear to be a consequence of the abnormal in vivo metabolic environment in the diabetic mice and not due to an intrinsic defect in the lymphoid cells themselves. The exact nature of the in vivo metabolic abnormalties responsible for the alterations in immunological function are unknown. The objectives of this proposal are: 1) To continue our in depth evaluation of immunological function in C57BL/KsJ-db+/db+ mice and mice with streptozotocin-diabetes mellitus. These studies will focus on suppressor T cell function, macrophage function and the humoral immune response to T-dependent and T-independent antigens; and 2) To further define the in vivo metabolic alterations responsible for the abnormalities in immuno- logical function in db/db and streptozotocin-diabetic mice. Specifically these investigations will a) evaluate in vivo transfer experiments whether spleen cells from nondiabetic db/m mice function normally in the diabetic milieu of the db/db mouse; b) determine whether restriction of food intake (with subsequent weight reduction) will: normalize in vivo immunological function and metabolic status in db/db mice; c) determine if zinc repletion of zinc deficient db/db mice will normalize in vivo immunological function; d) analyze the level and composition of serum and lymphocyte plasma membrane lipids, serum lipoproteins and lymphocyte plasma membrane fluidity in db/db and streptozotocin-diabetic mice; and e) determine whether the altered immunological function of diabetic mice is mediated by serum factor(s). These studies should provide important insights into the consequences of the diabetic state on immunological reactivity and may provide a useful model for the elucidation of the functional consequences of the diabetic state on cells of other organ systems.